Significant improvement in PFS versus systemic treatment.

Upfront autologous stem cell transplantation after high-dose induction chemotherapy resulted in a significant survival advantage for patients with newly diagnosed myeloma, as compared with induction plus additional chemotherapy, a randomized trial showed.

Overall, bortezomib (Velcade)-containing induction therapy followed by melphalan and stem-cell transplantation resulted in a 24% reduction in the hazard for disease progression or death at 36 months as compared with induction therapy plus four additional cycles of bortezomib-containing chemotherapy. The magnitude of the hazard reduction approached 50% for certain subgroups.

A second phase of the trial, involving randomization to consolidation therapy, has yet to be completed, Michele Cavo, MD, said during a press briefing prior to the American Society of Clinical Oncology meeting.
“We performed a multivariate analysis … and we found that randomization to upfront auto-transplant was an independent variable positively affecting patient outcomes,” said Cavo, of Bologna University in Italy. “In comparison to those patients who did not have an auto-transplant, those randomized to high-dose chemotherapy and upfront autologous stem cell transplantation had a significantly higher probability of achieving at least a 90% reduction in tumor burden.”
High-risk patients — including International Staging System (ISS) III and high-risk cytogenetics — appeared to derive the greatest benefit from auto-transplantation, he added.
During the discussion the followed Cavo’s presentation, the combination of drugs used for induction — bortezomib, cyclophosphamide, and dexamethasone (VCD) — came into question, as lenalidomide (Revlimid) is used more often than cyclophosphamide in the United States. Cavo responded that the different induction regimens have not been compared in randomized trials, so superiority of one versus the other remains uncertain. The primary message of the study relates to the superiority of upfront transplantation, he added.
Use of the VRD (sometimes called RVD) induction regimen — bortezomib, lenalidomide, and dexamethasone — might have led to different results, Noopur S. Raje, MD, of Massachusetts General Hospital Cancer Center in Boston, acknowledged in an email. Another European study reported at the 2015 American Society of Hematology meeting demonstrated superiority for upfront auto-transplantation when VRD induction therapy was used, she added.

Historically, autologous hematopoietic stem cell transplantation has represented the preferred treatment strategy for transplant-eligible patients with newly diagnosed myeloma. However, the introduction of immumodulatory agents (imids) and proteasome inhibitors has dramatically improved the rate of complete response in myeloma and significantly increased PFS and overall survival in previously untreated patients.
“In the current era, prospective comparisons of novel agent-based therapies versus auto-transplant, single versus double auto-transplant, and consolidation therapy versus no consolidation therapy are needed in patients with newly diagnosed multiple myeloma,” said Cavo. “These objectives were addressed in a large prospective, multicenter, intergroup, randomized phase III study, conducted by the European Myeloma Network.”
All patients started treatment with three to four cycles of VCD followed by randomization to four cycles of bortezomib-melphalan-prednisone (BMP) therapy or to melphalan plus auto-transplant. All patients received maintenance therapy with lenalidomide, and investigators randomized them a second time to VRD consolidation therapy or no consolidation. At centers that normally perform dual auto-transplants, patients were further randomized to one or two transplant procedures.
The trial had a primary endpoint of PFS. Cavo reported findings from the first randomized stage of the trial. Data analysis included 512 patients treated with chemotherapy and 754 randomized to auto-transplant. The report occurred after a median follow-up of 23.9 months.
The results showed a hazard ratio for progression or death of 0.76 in favor of the transplant group (95% CI 0.61-0.94, P=0.01). Subgroup analysis showed a consistent trend in favor of upfront transplantation. Significant differences emerged from analyses of patients with revised ISS III disease status (N=167, HR 0.52, 95% CI 0.32-0.85, P=0.01) and patients with high-risk cytogenetics (N=412, HR 0.72, 95% CI 0.54-0.97, P=0.03).
The multivariate analysis identified four independent predictors of PFS:
ISS 1 – HR 0.44, 95% CI 0.28-0.67, P<0.0001
Standard-risk cytogenetics – HR 0.57, 95% CI 0.41-0.78, P<0.0001
Randomization to auto-transplant – HR 0.61, 95% CI 0.45-0.82, P=0.001
<60% bone marrow plasma cells – HR 0.67, 95% CI 0.48-0.99, P=0.014
The complete response rate (stringent plus conventional) was similar for the chemotherapy (43.7%) and auto-transplant (41.6%) arms. However, significantly more patients in the transplant group achieved very good partial response or complete response (84.4% versus 74.0%, P<0.0001).